Biosynthesis of novel desferrioxamine derivatives requires unprecedented crosstalk between separate NRPS-independent siderophore pathways.

Iron is essential to many biological processes but its poor solubility in aerobic environments restricts its bioavailability. To overcome this limitation, bacteria have evolved a variety of strategies, including the production and secretion of iron-chelating siderophores. Here, we describe the discovery of four series of siderophores from Streptomyces ambofaciens ATCC23877, three of which are unprecedented. MS/MS-based molecular networking revealed that one of these series corresponds to acylated desferrioxamines (acyl-DFOs) recently identified from S. coelicolor. The remaining sets include tetra- and penta-hydroxamate acyl-DFO derivatives, all of which incorporate a previously undescribed building block. Stable isotope labeling and gene deletion experiments provide evidence that biosynthesis of the acyl-DFO congeners requires unprecedented crosstalk between two separate non-ribosomal peptide synthetase (NRPS)-independent siderophore (NIS) pathways in the producing organism. Although the biological role(s) of these new derivatives remain to be elucidated, they may confer advantages in terms of metal chelation in the competitive soil environment due to the additional bidentate hydroxamic functional groups. The metabolites may also find application in various fields including biotechnology, bioremediation, and immuno-PET imaging.IMPORTANCEIron-chelating siderophores play important roles for their bacterial producers in the environment, but they have also found application in human medicine both in iron chelation therapy to prevent iron overload and in diagnostic imaging, as well as in biotechnology, including as agents for biocontrol of pathogens and bioremediation. In this study, we report the discovery of three novel series of related siderophores, whose biosynthesis depends on the interplay between two NRPS-independent (NIS) pathways in the producing organism S. ambofaciens-the first example to our knowledge of such functional cross-talk. We further reveal that two of these series correspond to acyl-desferrioxamines which incorporate four or five hydroxamate units. Although the biological importance of these novel derivatives is unknown, the increased chelating capacity of these metabolites may find utility in diagnostic imaging (for instance, 89Zr-based immuno-PET imaging) and other applications of metal chelators.

Resilient responses to stressful events among chiropractic students: A cross-sectional survey.

OBJECTIVE: Resilient students may better navigate the challenges of chiropractic training. This study explored the relationships between response to stressful experiences, perceived stress, and quality of life among students at 1 US chiropractic college campus. METHODS: A cross-sectional survey was conducted with 873 students. The anonymous online questionnaire included demographics, quality of life, perceived stress, and the Response to Stressful Events Scale (RSES). Hierarchical multiple regression analyses assessed for significant relationships among variables. RESULTS: A sample of 221 students (60% female) completed the survey (25% response rate). Male respondents reported greater psychological health. Participants reporting high quality of life exhibited higher resiliency on the RSES flat score and many RSES domains. Respondents who rated greater psychological health and social relationships exhibited greater spiritual resiliency. Respondents reporting higher psychological health and lower levels of perceived stress exhibited higher self-efficacy resilience. Psychological health was the most important predictor for RSES flat score and domains, except for spiritual resilience, for which social relationships were most important. Male gender was predictive of 3 RSES domains: meaning making, active coping, and cognitive flexibility. CONCLUSION: More resilient responses to stressful events were reported by male chiropractic students and those who reported greater psychological health, higher quality of life, or lower perceived stress. Female students and those experiencing psychological challenges or lower quality of life might consider resilience training to increase the use of protective coping strategies. These findings may permit academic institutions to identify students at highest risk and employ interventions to prevent program withdrawal.

Adverse childhood experiences and trauma informed care for chiropractors: a call to awareness and action.

BACKGROUND: Trauma is an emotional response to distressing events where coping and subsequent recovery are absent. Adverse Childhood Experiences (ACEs) are traumas, occurring before the age of 18 years, such as child abuse or neglect, caregiver instability, and household dysfunction. Sixty-four percent of the U.S. population report experiencing at least one ACE, with over 1 billion children experiencing abuse and neglect annually worldwide. Chronic exposure to stressful circumstances or multiple traumatic events has negative physiologic impacts. Persons who experience 3 or more ACEs in childhood are at greater risk of poor mental health outcomes and may be more likely to engage in high-risk behaviors, predisposing them to long-term health impacts, such as metabolic diseases, anxiety, depression, substance use, and chronic pain. Trauma informed care (TIC) is a recommended approach to healthcare delivery across professions, especially when a trauma history is suspected. This commentary aims to increase awareness of the impact of ACEs on health outcomes and introduce TIC concepts as they may apply to chiropractic care for adults with a history of ACEs. DISCUSSION: This commentary reviews an introductory model (4R's: realize, recognize, respond, resist re-traumatization) as one TIC framework used by healthcare practitioners. Prior trauma can lessen trust, alter perceptions of physical touch, and hands-on examinations and chiropractic treatments may trigger stress responses. Using TIC after appropriate training, includes referrals to multidisciplinary providers to address trauma-related concerns outside the scope of chiropractic, and screening for ACEs if deemed appropriate. Creating safe spaces, communicating clearly, avoiding victimizing language, explaining procedures, asking for consent before physical contact, and giving patients choice and control in their own care may avoid triggering prior traumas. CONCLUSION: Given the high worldwide prevalence of persons experiencing 3 or more ACEs, TIC principles are practical adaptations to chiropractic care for use with many patient populations. As TIC and ACEs are emerging concepts within chiropractic, students and practitioners are encouraged to undertake additional training to better understand these complex and sensitive topics. Exploratory research on the incidence, presentation, and impacts of various trauma types, including ACEs, to support adoption of TIC in chiropractic settings is essential.

Author Correction: Insights into a dual function amide oxidase/macrocyclase from lankacidin biosynthesis.

In the original version of this Article, the final concentration of riboflavin in the supplemented LB medium for recombinant LkcE expression was incorrectly stated as 1 g L-1 (this was the concentration of the stock solution) and should have read 10-50 mg L-1. This error has been corrected in both the PDF and HTML versions of the Article.

Guided Hands-On Activities Can Improve Student Learning in a Lecture-Based Qualitative Biomechanics Course.

A qualitative biomechanics (functional anatomy) course is a typical course in kinesiology curriculum. Most evidence suggests that biomechanics learning could be improved with the inclusion of laboratory experiences. However, implementing laboratories into biomechanics curriculum is difficult due to cost and time constraints. This study was conducted to evaluate whether hands-on activities in lecture improve qualitative biomechanics learning. A lecture format was compared to the same course with guided and unguided hands-on activities included during lecture. Test performance and student evaluations were compared between lecture formats to determine if hands-on experiences improve learning. The hands-on group performed better on the same test questions and they evaluated their overall course activities as beneficial to their learning. The findings suggest that guided hands-on experiences may improve learning compared to unguided activities. The hands-on experiences seem to provide an embodied cognitive learning experience, facilitating retention of learned material through three-dimensional and tactile mental representations. Findings from this research are currently shaping how biomechanics is taught to students at this university and could at other universities as well.

High-dose vitamin C therapy for inclusion body myositis.

OBJECTIVES: The efficiency of high-dose vitamin C therapy for inclusion body myositis (IBM) was assessed. SUBJECTS & METHODS: The subjects were five patients with IBM confirmed pathologically. After the intravenous administration of 40 mg/kg vitamin C five times/week for four weeks, muscle weakness was found to improve in three cases. The average muscle score improved from 8.1 to 8.8, from 7.0 to 8.1 and from 6.2 to 6.8. Magnetic resonance imaging (MRI) demonstrated a reduction in the size of T2 high lesions and gadolinium enhancement in the thigh muscles in one case. Based on our findings, high-dose vitamin C therapy is considered to be effective in some cases of IBM.

[A patient with vitamin E deficient, myopathy presenting with amyotrophy].

We report a 61-year-old man with vitamin E deficiency, presenting with, myopathy as an only clinical symptom. In 1997, at 59 years of age, he noted mild proxymal-muscle weakness and atrophy in the four extremities, nine years after he received a Billroth II partial gastrectomy for a gastric ulcer. His muscle weakness slowly exacerbated, and he was admitted to our hospital in 1999. On admission, neurological examination confirmed mild proximal-muscle weakness and atrophy in the four extremities. Intelligence, cranial nerves, coordination, sensation and tendon reflexes were all normal. Laboratory examination showed normochromic anemia (Hb 9.9 g/dl, Ht 30.9%, MCV 97.5 fl, MCHC 31.2 pg), hypoproteinemia (5.0 g/dl), and hypocholesterolemia (107 mg/dl). The levels of serum CK, lactate and pyruvate were normal. The serum vitamin E level was markedly reduced (0.17 mg/dl; normal 0.75-1.41). Cerebrospinal fluid was normal. Nerve conduction, sensory evoked potentials (SEP), electromyography (EMG), head CT and electroencephalography (EEG) were all normal. Muscle biopsy from the right deltoid muscle showed both mild myogenic and neurogenic changes. Remarkably, type 1 muscle fiber predominance and granular accumulation of autofluorescent lipofuscin granules in the muscle fibers were found. These pathological findings were compatible with those of vitamin E-deficient myopathy. Thus, he was diagnosed as having vitamin E-deficient myopathy, which was confirmed by apparent effective supplementation of vitamin E. Interestingly, our present case did not show any other neurological manifestations such as deep sensory disturbance, sensory ataxia or polyneuropathy. A long-term workload due to hard physical labor and smoking in our patient may have accelerated oxidative muscle damage, resulting in amyotrophy mainly due to vitamin E deficient myopathy.

[A case of Lyme disease with the triad of neurologic manifestations (meningitis, radiculoneuritis, facial nerve palsy) and dermatitis of the nail roots].

A 23-year-old man experienced dysesthesia of the distal parts of four limbs and spilling of drinking water from the right corner of his mouth. He also experienced low grade fever, headache, and nausea. Neurological examination showed weakness of the right frontal, orbicularis oculi and orbicularis oris muscles, atrophy and weakness of the interosseous muscles in both upper limbs and dysesthesia in the distal parts of four limbs. Laségue's sign was also positive on the left side. Examination of CSF showed lymphocytic pleocytosis and an increase of total protein. Serum antibody against Borrelia garinii was positive as determined by ELISA. The patient was diagnosed as a case of Lyme disease. His symptoms were not alleviated by administration of ceftriaxone (2 g/day) for 15 days, and dermatitis of nail roots appeared. Following administration of penicillin G at a high dose (12 million units/day) for 20 days, both neurologic symptoms and dermatitis were alleviated. Since B. garinii was reported to move preferentially toward the sites of low temperature, dermatitis of nail roots may be one of the characteristic features of Lyme disease caused by B. garinii.

Two CPT2 mutations in three Japanese patients with carnitine palmitoyltransferase II deficiency: functional analysis and association with polymorphic haplotypes and two clinical phenotypes.

Carnitine palmitoyltransferase II (CPT II) deficiency manifests as two different clinical phenotypes: a muscular form and a hepatic form. We have investigated three nonconsanguineous Japanese patients with CPT II deficiency. Molecular analysis revealed two missense mutations, a glutamate (174)-to-lysine substitution (E174K) and a phenylalanine (383)-to-tyrosine substitution (F383Y) in the CPT II cDNA. Transfection experiments in COS-1 cells demonstrated that the two mutations markedly decreased the catalytic activity of mutant CPT II. Case 1 (hepatic form) was homozygous for the F383Y mutation, whereas case 3 (muscular form) was homozygous for the E174K mutation. Case 2 and her brother, who were compound heterozygotes for E174K and F383Y, exhibited the hepatic phenotype. We also identified a novel polymorphism in the CPT2 gene, a phenylalanine (352)-to-cysteine substitution (F352C), which did not alter CPT II activity in transfected cells. It was present in 21 out of 100 normal alleles in the Japanese population, but absent in Caucasian populations. Genotyping with the F352C polymorphism and the two previously reported polymorphisms, V368I and M647V, allowed normal Japanese alleles to be classified into five haplotypes. In all three families with CPT II deficiency, the E174K mutation resided only on the F1V1M1 allele, whereas the F383Y mutation was observed on the F2V2M1 allele, suggesting a single origin for each mutation.

[A patient with liver cirrhosis manifesting various symptoms including cerebellar ataxia due to germanium intoxication].

A patient with hepatitis B virus-associated cirrhosis manifested various symptoms such as anemia, renal damage and neurological signs including cerebellar ataxia due to long-term administration of germanium-containing food. The patient was a 40-year-old male who had taken germanium containing mineral cheese for 26 months after he was diagnosed as having cirrhosis. Twenty four months after beginning to take the mineral cheese, he began manifesting paresthesia of the extremities, dysarthria and gait ataxia. Laboratory findings revealed anemia and renal damage. Biopsy of the peripheral nerve revealed loss of the large sheathed nerve, a characteristic feature of germanium intoxication. A high concentration of germanium (GeO2) was detected in patient's hair and urine. Cerebellar ataxia was characteristic in this patient, which was not reported in the previous papers.

Hyperprolactinemia in multiple sclerosis.

In order to clarify endocrine abnormalities due to hypothalamic involvement in multiple sclerosis (MS), serum prolactin levels were measured in 27 patients with MS and 22 healthy subjects. The presence of hypothalamic lesions was also studied by magnetic resonance imaging (MRI). Serum prolactin levels were found to be significantly higher in MS patients than in healthy controls in both sexes. Although only one patient had galactorrhea, one-third of the MS patients had mild to moderate hyperprolactinemia, which was a 4-13-fold increase over the mean value of healthy subjects. The results of thyrotropin-releasing hormone, sulpiride, L-DOPA and bromocriptine loading tests suggested a hypothalamic dysfunction, rather than pituitary prolactinoma in MS patients. Four of eight patients with hyperprolactinema had diencephalic hypothalamic lesion(s) contiguous with the third ventricle on the brain MRI, while none of the normoprolactinemic patients had any lesions in the diencephalon. All relapsing-remitting patients with hyperprolactinemia showed a rise in prolactin levels in the acute stage of the relapse and a decrease during the recovering stage and the following remission phase. Our findings suggest that latent hyperprolactinemia due to hypothalamic dysfunction occurs frequently in MS patients in relapse. The increase of serum prolactin is considered to be a sensitive indicator for hypothalamic lesions in MS.